Toward an integrated map of genetic interactions in cancer cells
Abstract Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype‐dependent vulnerabilities, forward genetic screens in different genetic...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-02-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20177656 |
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| author | Benedikt Rauscher Florian Heigwer Luisa Henkel Thomas Hielscher Oksana Voloshanenko Michael Boutros |
| author_facet | Benedikt Rauscher Florian Heigwer Luisa Henkel Thomas Hielscher Oksana Voloshanenko Michael Boutros |
| author_sort | Benedikt Rauscher |
| collection | DOAJ |
| description | Abstract Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype‐dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cells combining functional data with information on genetic variants to explore more than 2.1 million gene‐background relationships. In addition to known dependencies, we identified new genotype‐specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities identified GANAB and PRKCSH as new positive regulators of Wnt/β‐catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic interactions in cancer, which can grow dynamically as more data are included. |
| format | Article |
| id | doaj-art-976451cedcc74a589433ae90e6e6e00f |
| institution | OA Journals |
| issn | 1744-4292 |
| language | English |
| publishDate | 2018-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-976451cedcc74a589433ae90e6e6e00f2025-08-20T02:11:54ZengSpringer NatureMolecular Systems Biology1744-42922018-02-0114211710.15252/msb.20177656Toward an integrated map of genetic interactions in cancer cellsBenedikt Rauscher0Florian Heigwer1Luisa Henkel2Thomas Hielscher3Oksana Voloshanenko4Michael Boutros5Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ)Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ)Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ)Division of Biostatistics, German Cancer Research Center (DKFZ)Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ)Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ)Abstract Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype‐dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cells combining functional data with information on genetic variants to explore more than 2.1 million gene‐background relationships. In addition to known dependencies, we identified new genotype‐specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities identified GANAB and PRKCSH as new positive regulators of Wnt/β‐catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic interactions in cancer, which can grow dynamically as more data are included.https://doi.org/10.15252/msb.20177656cancerepistasisgenetic interactionsnetworkssynthetic lethality |
| spellingShingle | Benedikt Rauscher Florian Heigwer Luisa Henkel Thomas Hielscher Oksana Voloshanenko Michael Boutros Toward an integrated map of genetic interactions in cancer cells Molecular Systems Biology cancer epistasis genetic interactions networks synthetic lethality |
| title | Toward an integrated map of genetic interactions in cancer cells |
| title_full | Toward an integrated map of genetic interactions in cancer cells |
| title_fullStr | Toward an integrated map of genetic interactions in cancer cells |
| title_full_unstemmed | Toward an integrated map of genetic interactions in cancer cells |
| title_short | Toward an integrated map of genetic interactions in cancer cells |
| title_sort | toward an integrated map of genetic interactions in cancer cells |
| topic | cancer epistasis genetic interactions networks synthetic lethality |
| url | https://doi.org/10.15252/msb.20177656 |
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